SAN DIEGO — Patients with idiopathic pulmonary fibrosis (IPF) had significant improvements in lung function and reversal of lung fibrosis measures after 12 weeks of therapy with an investigational inhibitor of the Hedgehog signaling pathway.
Early efficacy data from a phase 2a safety trial suggest that the novel oral agent dubbed ENV-101 is associated with improvements in forced vital capacity (FVC) and other measures of lung function and may be a disease-modifying therapy for IPF, according to Toby M. Maher, MD, PhD, director of Interstitial Lung Disease in the Keck School of Medicine at the University of Southern California in Los Angeles.
“Historically we’ve not been seeing improvements in FVC, which is what we’ve been seeing [with ENV-101], and I think it’s conceivable that you can get remodeling of early areas of fibrosis in the lung,” Maher said in an interview.
“We know from histology studies that if you look at IPF lungs you’ll see areas of end-stage fibrosis, but even in advanced disease, you’ll see areas where the lung is relatively well preserved and there’s early fibrosis, so I think it’s conceivable that there is remodeling of some of those early areas of fibrosis,” he said.
Vital Pathway
The Hedgehog pathway is highly conserved in evolution. The cell-signaling pathway is active in embryogenesis, tissue proliferation, and organ development. There is also evidence to suggest that in adults, the pathway becomes reactivated after tissue injury, which can occur in lung epithelia, Maher explained.
Although as the word idiopathic in IPF indicates, the etiology of the disease is unknown; investigators have found that in IPF, repetitive epithelial injury to lung tissue leads to activation of the Hedgehog pathway. Hedgehog signaling, in turn, induces formation and activation of myofibroblasts that lay down fibrotic matrix and contract lung tissue, leading to significant impairments in gas exchange, Maher said.
ENV-101 blocks Hedgehog from binding to the PTCH1 receptor, thus preventing release of the zinc-finger protein GLI1 from the kinase complex into the cell cytoplasm. With signaling blocked, myofibroblasts undergo apoptosis instead of initiating wound repair as they normally would, thereby eliminating an evident mechanism of IPF pathology, he explained.
Study Details
In the phase 2a trial, investigators enrolled patients with IPF who were not taking antifibrotic agents and who had a percent-predicted FVC of greater than 50%, percent-predicted diffusing capacity for carbon monoxide of at least 35%, and life expectancy of more than 1 year.
The patients were randomly assigned to receive 200-mg oral ENV-101 daily (18 patients) or placebo (15 patients) for 12 weeks.
The primary endpoint of the trial was safety of the experimental agent. (A previous phase 1b study of a different Hedgehog inhibitor, vismodegib [Erivedge], in combination with the antifibrotic agent pirfenidone [Pirespa] in patients with IPF was discontinued due to poor tolerability.)
In the current study, the most common treatment-related adverse events were dysgeusia in 57% of patients who received the drug, alopecia in 52%, and muscle spasms in 43%. The spasms were generally less severe than were those seen in the vismodegib-pirfenidone trial mentioned above.
Seven patients (33%) had treatment-emergent events leading to dose interruption. Five patients discontinued treatment, including one who withdrew due to taste alterations, one who was lost to follow-up after an IPF exacerbation, and three who withdrew consent.
There were no treatment-related deaths and no clinically significant findings on labs, vital signs, electrocardiograms, or physical examination.
Efficacy Endpoints
An analysis of the secondary efficacy endpoints showed a 1.9% mean improvement in FVC from baseline among patients assigned to ENV-101 compared with a mean decline of 1.3% among patients assigned to placebo (P =.035).
Patients on the active drug also had 200-mL mean increase in total lung capacity compared with a mean decline of 56 mL for patients on placebo (P =.005).
In addition, high-resolution CT studies also showed a 9.4% absolute decrease from baseline in quantitative interstitial lung disease with ENV-101 vs a 1.1% increase with placebo, a 2% absolute decline from baseline in quantitative lung fibrosis compared with a 0.87% increase with placebo, and a 4.6% absolute decrease from baseline in quantitative ground glass compared with an increase of 0.29% with placebo.
Bad Taste a Good Sign?
Reinoud Gosens PhD, University of Groningen, the Netherlands, who co-moderated the session but was not involved in the study, questioned whether the dysgeusia seen in patients who received ENV-101 might be related to the dysgeusia seen in clinical trials of P2X3 receptor antagonists for cough.
“I was wondering if there would be a mechanistic overlap between Hedgehog inhibition and cough, which would be quite relevant for IPF,” he said in an interview.
The increase in FVC seen with ENV-101 and with the investigational agent buloxibutid, a novel angiotensin II type 2 receptor agonist described in a separate presentation by Maher, suggests that these drugs may have the ability to help remodel damaged lungs, Gosens said.
Investigators are currently planning a phase 2 dose-ranging trial (WHISTLE-PF) in patients with IPF or progressive pulmonary fibrosis.
The phase 2a trial was supported by Endeavor BioMedicines. Maher disclosed consultancy or speaker fees from Endeaveor and others. Grosen had no relevant disclosures.
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